Hepatitis C virus (HCV) infects 170 million people worldwide and exacts a heavy toll on global health. Diseases caused by chronic HCV infection include acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HCV infection also correlates with high prevalence of fatty liver (steatosis) in patients, which may account for many metabolic disorders such as insulin resistance and diabetes mellitus. Combination therapy with polyethylene glycol modified IFN-a and ribavirin suppresses HCV replication in 40-80% of patients. However, severe side effects are associated with this treatment, leading to poor patient compliance. For these reasons, it is crucial to develop effective vaccine and alternative therapies, a goal that cannot be accomplished without a better understanding of the HCV virology. Interestingly, recent studies have linked host cholesterol and fatty acid metabolic pathways to HCV life cycle. We have reported that HCV infection upregulates fatty acid synthase (FASN), the key enzyme carrying out de novo lipogenesis. We also demonstrated that HCV infection requires FASN activity. Subsequently we found that HCV- infected human hepatoma cells increased their expressions of hepatic lipase (HL) and lipoprotein lipase (LPL), both of which are key enzymes in maintaining circulating lipoprotein levels and can facilitate lipid uptake via their associations with heparin sulphate proteoglycans (HSPG) on hepatocyte surface. Because it is known that HSPG mediates the initial HCV attachment and circulating HCV associates with lipoproteins, we hypothesize that elevated levels of HL and LPL may regulate the HCV infection and production in either cell-bound forms or secreted forms. Two specific aims are designed to address that hypothesis: (i) To determine the roles of cell-bound HL and LPL in HCV infection. (ii) To evaluate the effect of elevated HL and LPL activities on circulating virus infectivity. Accomplishing these objectives will provide a better understanding of HCV life cycle and the HCV-associated steatosis with implications for the development of novel antiviral therapeutics. PUBLIC HEALTH RELEVANCE: Chronic HCV infection strongly correlates with lower plasma cholesterol levels and the accumulation of fat in livers (steatosis), a state preceding many liver diseases owing to its intimate association with obesity and insulin-resistant diabetes mellitus. Completion of the proposed research will shed light to our understanding of the underlying mechanisms of HCV-associated steatosis and the HCV life cycle. Such knowledge is critical for the future development of novel antiviral therapies.